Process for the preparation of substituted 8-azabicyclo[3,2,1]octanes

ABSTRACT

A process for preparing a compound of formula (IV) wherein R 1  is C 1-4  alkyl, C 1-4  haloalkyl, benzyl, C 3-6  alkenyl or C 3-6  alkyny, (provided that the α-carbon atom of R 1  is neither unsaturated nor substituted with halogen), which comprises reacting a compound of formula (III) with a source of hydroxylamine in the presence of an acid. Compounds of formula (IV) are agrochemical intermediates.

CROSS-REFERENCE

This application is a 371 of PCT/GB98/03635 filed Dec. 27, 1998.

The present invention concerns a process for preparing3-cyano-8-substituted-8-azabicyclo[3.2.1]octanes.3-Cyano-8-substituted-8-azabicyclo[3.2.1]octanes are useful asintermediates for certain insecticides (see, for example, WO 96/37494).

The present invention provides a process for preparing a compound offormula (IV), wherein R¹ is C₁₋₄ alkyl, C₁₋₄ haloalkyl, benzyl, C₃₋₆alkenyl or C₃₋₆ alkynyl (provided that the α-carbon atom of R¹ isneither unsaturated nor substituted with halogen), which comprisesreacting a compound of formula (III) with a source of hydroxylamine inthe presence of an acid. A preferred source of hydroxylamine ishydroxylamine hydrochloride or hydroxylamine itself. Suitable acids thatcan be used for this reaction include organic acids (such as formic acidor acetic acid) or mineral acids (such as hydrochloric acid, nitric acidor sulphuric acid).

In one particular aspect the present invention provides a process forpreparing a compound of formula (IV), wherein R¹ is as defined above,comprising the steps:

i. ring opening a compound of formula (II) to give a compound of formula(III); and,

ii. reacting a compound of formula (III) with a source of hydroxylaminein the presence of an acid.

It is preferred that the ring opening of a compound of formula (II) isby reacting it with a strong organic acid (such as trifluoroaceticacid).

In another aspect the present invention provides a process for preparinga compound of formula (IV), wherein R¹ is as defined above, comprisingthe steps:

i. converting a compound of formula (I) to a compound of formula (II) bya methylene insertion reaction;

ii. ring opening a compound of formula (II) to give a compound offormula (III); and,

iii. reacting a compound of formula (III) with a source of hydroxylaminein the presence of an acid.

It is preferred that the compound of formula (I) is converted to acompound of formula (II) by reacting it with a suitable sulphur ylid(such as that generated by reacting trimethylsulphoxonium iodide and analkali metal hydride (for example sodium hydride)).

Alkyl groups may be straight or branch chains are, for example, methylethyl, n-propyl or iso-propyl.

Haloalkyl is preferably alkyl optionally substituted with chlorine orfluorine and is, for example, 2,2,2-trifluoroethyl or 2,2-difluoroethyl.

Alkenyl and alkynyl groups are, for example, allyl or propargyl.

A compound of formula (II) can be prepared by adding a compound offormula (I) to a sulphur ylid (such as the ylid formed by the reactionof sodium hydride with trimethylsulphoxonium iodide), the reaction beingcarried out in a suitable solvent (such as tetrahydrofuran) and at asuitably elevated temperature (preferably in the range 50-100° C., suchas at the boiling point of the solvent used).

A compound of formula (III) can be prepared by ring opening a compoundof formula of formula (II) under acidic conditions (such as with anorganic acid (preferably acetic acid or, especially, trifluoroaceticacid) or a suitable ion exchange resin (for example an Amberlyst®resin)) in a suitable solvent (such as toluene) and at a suitablyelevated temperature (such as between 50° C. and the boiling point ofthe solvent used).

A compound of formula (IV) can be prepared by reacting a compound offormula (III) with hydroxylamine hydrochloride in the presence of anacid, which may also act as a solvent (such as formic acid) at asuitably elevated temperature (such as between 50° C. and the boilingpoint of the solvent used).

In another aspect the present invention provides a process for preparinga compound of formula (IV) which comprises the steps:

i. reacting a compound of formula (I) with a sulphur ylid (preferablyformed by the reaction of sodium hydride with trimethylsulphoxoniumiodide) at 50-100° C. to give a compound of formula (II);

ii. ring opening a compound of formula (II) under acidic conditions andat a temperature in the range 50-120° C. to give a compound of formula(III); and,

iii. reacting a compound of formula (III) with hydroxylaminehydrochloride in the presence of an acid and at a temperature in therange 50-120° C.

A compound of formula (A) can be prepared by reacting a compound offormula (IV) with a compound R²L, wherein R² is pyridyl optionallysubstituted with halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, C₂₋₄ alkenylor C₂₋₄ alkynyl, and L is a suitable leaving group (such as halogen ormesylate). Thus, in a further aspect the present invention provides acompound of formula (A) when made by reacting a compound of formula (IV)(as prepared by a process as hereinbefore described) with a compoundR²L.

A compound of formula (A), wherein R¹ is C₁₋₄ alkyl, C₁₋₄ haloalkyl,benzyl, C₃₋₆ alkenyl or C₃₋₆ alkynyl (provided that the β-carbon atom ofR¹ is neither unsaturated nor substituted with halogen), and R² ispyridyl optionally substituted with halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,cyano, C₂₋₄ alkenyl or C₂₋₄ alkynyl, when prepared by a processcomprising the steps:

i. reacting a compound of formula (III) with a source of hydroxylaminein the presence of an acid to provide a compound of formula (IV); and,

ii. reacting a compound of formula (IV) with a compound R²L, wherein Lis a suitable leaving group (such as halogen or mesylate).

In a further aspect the present invention provides a compound of formula(II) wherein R¹ is CH₂CHF₂ or CH₂CF₃.

In a still further aspect the present invention provides a compound offormula (III) wherein R¹ is CH₂CHF₂ or CH₂CF₃.

The following Example illustrate the invention. Selected NMR data andmass spectral data are presented in the Examples. For NMR data, noattempt has been made to list very absorption. The followingabbreviations are used throughout the Examples:

m = multiplet ppm = parts per million THF = tetrahydrofuran q = quartets = singlet

EXAMPLE 1

This Example illustrates the preparation of3-cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane.

Step 1

A dry 500 ml 3-necked round bottom flask was fitted with a pressureequalised dropping funnel, nitrogen bubbler, thermometer, refluxcondenser and mechanical stirrer. Sodium hydride (7.84 g, 0.32 mol) wascharged to the reaction flask followed by trimethyl sulphoxonium iodide(71.7 g, 0.32 mol). Dry THF (200 ml) was charged to a dropping funneland then added over 0.25 hour. The mixture was agitated at ambient for0.5 hour, during which time hydrogen evolved gently.8-(2,2,2-Trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-one (50 g, 0.23 mol)in dry THF (50 ml) was added to the mixture after which the mixture wasrefluxed for 4 hours. After this time, the THF was removed by rotaryevaporation, then saturated sodium metabisulphite (200 ml)) was added.Hexane (100 ml) was added and separated and the aqueous later was washedwith hexane (2×100 ml). The organic extracts were combined, dried(MgSO₄) and evaporated in vacuo to give a crude sample of a compound offormula (II) wherein R¹ is CF₃CH₂ which was purified by distillation(58° C. @ 2 mmHg) to leave a colourless oil (36 g, 68% yield).

¹H NMR (CDCl₃): δ 1.10-1.25(m,2H), 1.85-2.15(m,4H), 2.35-5.50(m,2H),2.45(s,2H), 2.95(q,2H), 3.30-3.40(m,2H)ppm.

¹³C NMR (CDCl₃): δ 27(s), 39(s), 49(s), 55(q), 62(s), 66(s), 126(q)ppm.

Mass spectral data: 221 (M⁺), 220, 192, 156, 150, 110.

Step 2

A 25 ml 3-necked round bottom flask was fitted with a reflux condenser,thermometer and magnetic stirrer and placed under a nitrogen atmosphere.The product of Step 1 (0.5 g, 2.1 mmol) and dry toluene (15 ml) werecharged to the flask after which trifluoroacetic acid (0.33 ml, 4.2mmol) was added dropwise. The reaction was agitated at room temperaturefor 1 hour and then refluxed for 1 hour. The reaction mass was cooled toambient, dichloromethane (40 ml) was added and the mixture then washedwith aqueous sodium bicarbonate (3×20 ml, 10%). The combined organicswere dried (MgSO₄) and concentrated in vacuo to give3-formyl-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octanepredominantly as the equatorial epimer (0.44 g, 54% yield). Purificationby column chromatography (silica, 40/60 diethyl ether:hexane) gave3-formyl-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane as a yellowsolid.

¹H NMR (CDCl₃) δ 1.55-2.10(m,8H), 2.40-2.55(m,1H), 2.90(q,2H),3.30-3.45(m,2H), 9.60(s,1H)ppm.

Mass spectral data: 221(M⁺), 192, 156, 150, 110.

Step 3

To a 25 ml round bottom flask fitted with a reflux condenser, magneticstirrer and a thermometer was charged formic acid (5 ml). The apparatuswas filled with nitrogen. To this was charged3-formyl-8-(2,2,2-trifluoroethyl)-8-azabicyclo([3.2.1]octane (0.235 g,0.9 mmol) and hydroxylamine hydrochloride (0.083 g, 1.2 mmol) and thereaction mixture was refluxed for 1 hour. The reaction mixture wascooled to ambient, water was added (20 ml) and the mixture was thenneutralised (with cooling) by the addition of saturated sodiumbicarbonate solution (2 ml). The resulting mixture was extracted withdiethyl ether (3×20 ml), and the combined organics were dried (MgSO₄)and concentrated by rotary evaporation to give the title compoundpredominantly as the equatorial isomer (0.178 g, 74% yield).

¹H NMR (CDCl₃): δ 1.50-2.15(m,8H), 2.65-2.85(m,1H), 2.85(q.2H),3.30-3.40(m,2H)ppm.

Mass spectral data: 218(M⁺), 199, 189, 164, 150.

EXAMPLE 2

This Example illustrates the preparation of3-formyl-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane.

A 100 ml 3-necked round bottom flask was fitted with a reflux condenser,thermometer and magnetic stirrer and the apparatus was filled withnitrogen. A compound of formula (II) wherein R¹ is CF₃CH₂ (1.5 g, 6.5mmol) and dry toluene (30 ml) were charged to the flask, followed byAmberlyst®-15 ion exchange resin (0.45 g). The reaction was stirred atroom temperature for 1 hour and then refluxed for 5.5 hour. The reactionmass was cooled to 40° C. and filtered to remove the Amberlyst® resin.Concentration in vacuo gave the title product predominantly as the axialepimer (1.06 g, 49% yield). Purification by short-path distillation (0.7mmHg, 56° C.) gave the title product as a colourless mobile oil (0.48 g,26% yield).

EXAMPLE 3

This Example illustrates the preparation of3-formyl-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane.

A 100 ml 3-necked round bottom flask was fitted with a reflux condenser,thermometer and magnetic stirrer and the apparatus was filled withnitrogen. A compound of formula (II) wherein R¹ is CF₃CH₂ (2.0 g, 8.2mmol), dry toluene (40 ml), and acetic acid (1.0 g, 17 mmol) werecharged to the flask and the reaction mixture was heated to reflux for0.5 hour. The heat source was removed and trifluoroacetic acid (0.19 g,1.6 mmol) added to the reaction (via syringe/septum under the surface ofthe liquid). The reaction mixture was refluxed for 0.75 hour beforecooling to ambient. The reaction mass was poured slowly onto a stirredsaturated, aqueous solution of sodium bicarbonate (150 ml), the pH wasadjusted to 8 with further saturated, aqueous solution of sodiumbicarbonate (50 ml) and the aqueous extracted with CH₂Cl₂ (3×50 ml). Thecombined organics were dried (Na₂SO₄), filtered, and concentrated invacuo to give the title product predominantly as the equatorial epimer,as a red/brown sticky tar (1.7 g, 44% crude yield).

¹H NMR (CDCl₃): δ 1.55-2.10(m.8H), 2.40-2.55(m, 1H), 2.90(q,2H),3.30-3.45(m,2H), 9.60(m, 1H)ppm.

Mass spectral data: 221 (M⁺), 192, 156, 150, 110.

EXAMPLE 4

This Example illustrates the preparation of a compound of formula (II)wherein R¹ is CF₃CF₂.

tert-Butyl alcohol (2 ml) and water (1 ml) were added todimethylsulphide (1.5 g, 23.6 mmol) in a 50 ml 3-necked flask, fittedwith septum inlet and stirrer bar. This mixture was stirred at ambienttemperature, with portionwise addition of dimethylsulphate (1.5 g, 11.8mmol) neat via syringe over 10 minutes. A slight exotherm was observedduring this addition, and the temperature was maintained between 20-25°C. with a cold water bath. The reaction mixture was stirred for 1 hour,then (2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-one (2.5 g, 11.8mmol, starting material) was added in one batch, along with portionwiseaddition of potassium hydroxide (1.32 g, 23 mmol) over 15 minutes, againmaintaining the temperature between 20-25° C. As the potassium hydroxidedissolved, the mixture turned from yellow/orange to red. The mixture wasstirred vigorously at ambient temperature for 19 hours after which timegc analysis showed 47% starting material remaining. Furtherdimethylsulphate (0.5 ml) and potassium hydroxide (0.5 g) were added tothe reaction mixture, which was stirred at ambient for an additional 6hours. The mixture was then diluted with water (10 ml), stirred for ½hour, and the resulting emulsion extracted twice with toluene. Theorganic extracts were combined, washed three times with aqueous sodiumchlorate, once with water and once with saturated brine, and they werethen concentrated under reduced pressure to leave a yellow/orange liquid(1.9 g). Analysis (gc) showed this to include the title compound (41%),starting material (29%) and some unidentified by-products.

What is claimed is:
 1. A process for preparing a compound of formula(IV):

(wherein R¹ is C₁₋₄ alkyl, C₁₋₄ haloalkyl benzyl, C₃₋₆ alkenyl or C₃₋₆alkynyl (provided that the α-carbon atom of R¹ is neither substrate norsubstituted with halogen), which comprises: i. ring opening a compoundof formula (II):

under acidic conditions in the presence of an organic acid or an ionexchange resin, in a suitable solvent and at a temperature between 50°C. and the boiling point of the solvent used, to give a compound offormula (III):

and, ii. reacting the compound of formula (III) with a source ofhydroxylamine in the presence of an acid.
 2. A process for preparing acompound of formula (IV) as claimed in claim 1 which comprises thesteps: i. converting a compound of formula (I):

wherein R¹ is as defined in claim 1, to a compound of formula (II) by amethylene insertion reaction; ii. ring opening a compound of formula(II) under acidic conditions in the presence of an organic acid or anion exchange resin, in a suitable solvent and at a temperature between50° C. and the boiling point of the solvent used, to give a compound offormula (III); and, iii. reacting a compound of formula (III) with asource of hydroxylamine in the presence of an acid.
 3. A process forpreparing a compound of formula (IV) as claimed in claim 1 whichcomprises the steps: i. reacting a compound of formula (I) with asulphur ylid at 50-100° C. to give a compound of formula (II); ii. ringopening a compound of formula (II) under acidic conditions in thepresence of an organic acid or an ion exchange resin, in a suitablesolvent and at a temperature in the range 50-120° C. to give a compoundof formula (III); and, iii. reacting a compund of formula (III) withhydroxylamine hydrochloride in the presence of an acid and at atemperature in the range 50-120° C.
 4. A process as claimed in claim 1,wherein R¹ is CH₂CHF₂ or CH₂CF₃.
 5. A compound of formula (II) or (III):

wherein R¹ is CH₂CHF₂ or CH₂CF₃.